Infection with Leishmania causes significant morbidity and mortality worldwide. The type of Leishmania species infecting the host and the immune response generated by the host determines the spectrum of clinical disease that is seen. In particular, the pattern of cytokine production from T cells is critical for protection. At present there is no vaccine for Leishmania that is easy to administer, efficacious, and cost effective. These experiments will seek to establish a vaccine regimen that is sufficient to confer long-term protective immunity following infectious challenge in mice and primates. Experiments will specifically focus on DNA, protein and recombinant viral vaccines. In addition, these studies will evaluate the cellular and molecular mechanisms by which different vaccine formulations induce long-term protective cellular immunity. Over the past year we have determined the following.[unreadable] [unreadable] 1. The quality of a Th1 response differs between adenoviral and protein/ TLR ligand based vaccines.[unreadable] 2. Multi-functional Th1 responses which secrete IL-2, TNF and IFN-g are correlated with protection and optimal effector cells.[unreadable] 3. Effector memory Th1 responses secrete IL-2 as well as IFN-g and TNFa.[unreadable] 4. IL-10 influences the magnitude and quality of Th1 responses following protein+ CpG immunization.[unreadable] 5. Adenovirus Type 5 immunization encoding a leishmanial antigen induces a high frequency of IL-10 producing CD4+ T cells with or without IFN-g.[unreadable] 6. IL-12 enhances the magnitude of multi-functional IFN-g producing CD4+ T cells following protein + CpG immunization.